The Debate Over Safe Injection Sites

BY PHILIP M. BOFFEY

IN THE FINAL WEEKS OF HIS administration, Bill de Blasio, then mayor of New York, opened the nation’s first two overdose prevention centers to save the lives of people with substance use disorders who inject dangerous narcotics. Such sites are almost certainly illegal under an outdated federal law designed to close places where drug use is prevalent. But is it also unethical or immoral to operate the new sites? Or would it be even more unethical to close them down and leave people struggling with addiction to the mercy of the streets?

The section of federal law that seemingly prohibits such sites makes it a felony to own, rent, or operate a location for the purpose of facilitating illegal drug use. Violators can be punished by up to 20 years in prison and served hefty fines. Simply raising that threat was enough to deter Philadelphia from opening a planned site.

There were more than 95,000 drug overdose deaths in the year ending in February 2021, an all-time record, according to the Centers for Disease Control and Prevention. The chief culprits were opioids, including fentanyl, heroin, and prescription opioids, among others.

The federal statute—dating back to the Anti-Drug Abuse Act of 1986— was designed to close buildings where people would shoot up and often die in shadowy corners in scenes worthy of a Dickens novel.

But the clean, modern facilities that federal authorities are targeting seem a much better option. The new facilities are sometimes called “safe injection sites” or “overdose prevention sites’” to underscore their important public health mission.

Shortly after New York City’s first two sites opened in November 2021, reporters for the New York Times described the scene inside. People brought their own drugs to the sites, were provided with clean needles to use, and if they overdosed, were quickly given naloxone to reverse the overdose and save their lives. They were also told about options to receive treatment for their addiction, often crucial information for people struggling with substance use disorders. The sites have been supported by four of the city’s five district attorneys and by Eric Adams, the new mayor, who has a strong police background. The local law enforcement authorities can draw on their experience to understand what cities desperately need to combat rising addiction rates.

The arguments against such sites were laid out by Rod Rosenstein, then deputy attorney general for the Trump administration, in an opinion piece in the New York Times on August 27, 2018. He called the sites “very dangerous” and said they “would only make the opioid crisis worse.” He claimed drug dealers would flock to the area, destroying the surrounding community. People “do not need a tax-payer sponsored haven to shoot up,” he said. “Injection sites normalize drug use and facilitate drug addiction by sending a powerful message to teenagers that the government thinks illegal drugs can be used safely.”

Some opponents of injection sites also raise moral arguments—saying that injection drug use is intrinsically evil because it is nontherapeutic and causes serious harm to the user. They believe injection sites entice some users to continue by providing them a site to shoot up. Interestingly, Rod Rosenstein did not make a moral or ethical argument but rather predicted dire consequences if sites are opened.

Regardless, observers on both sides of the discussion need to choose appropriate language to reduce stigma and avoid undermining the likelihood that people will seek help. A paper published in Neuropsychopharmacology indicates that “stigma—negative attitudes toward people based on distinguishing characteristics— contributes in multiple ways to poorer health outcomes; consequently, it has been identified as a critical focus for research and interventions.”

On the opposite side of this debate, William F. Haning III, a physician in Hawaii, made a strong case for supporting injection sites in a September 29, 2021, opinion piece the spread of blood-borne infectious diseases.

The trend nationwide is running toward greater use of injection sites. Rhode Island last year became the first state to enact a law to open sites with local approval under a for STAT news. Writing as president of the American Society of Addiction Medicine, he cited great value in opening sites where people can consume previously obtained drugs in a hygienic monitored environment without fear of arrest. The American Medical Association has also endorsed such sites.

Haning cited research in other nations which showed that injection sites did not increase drug use, trafficking, or crime. Instead of destroying the surrounding community, the sites reduced the volume of public injecting as well as the number of syringes discarded on streets and sidewalks. On the plus side, the sites achieved important health goals by reducing harm among drug users and connecting some to health and social services. The sites are no panacea, of course, and can’t solve all the societal factors that contribute to drug use. But they can at least reduce deaths and provide clean needles to prevent two-year pilot program. San Francisco is poised to open a site later this year, and other cities are expected to join the parade. The Boston Globe editorial board called for their own mayor to follow quickly on the heels of New York.

Whether the Biden administration will be more receptive than the Trump administration to safe injection sites and other harm reduction approaches is not yet clear. The president may be too preoccupied with a host of domestic and foreign crises and political battles to pay much attention to this issue. His staff and cabinet appointees would be wise to recognize that the most ethical course of action would be to open more of these sites and pledge not to arrest their staff or clientele working to combat addiction and save lives. l

PHIL BOFFEY is former deputy editor of the New York Times Editorial Board and editorial page writer, primarily focusing on the impacts of science and health on society. He was also editor of Science Times and a member of two teams that won Pulitzer Prizes in poverty show tangible alterations. Our authors, all part of needed to build a healthier and more productive society.

The views and opinions expressed are those of the author and do not imply endorsement by the Dana Foundation.

By Joan L. Luby, M.D., John N. Constantino, M.D., & Deanna M. Barch, Ph.D.

Numerous studies of children in the US across decades have shown striking correlations between poverty and less-thanoptimal physical and mental health and developmental outcomes. Trauma, poor health care, inadequate nutrition, and increased exposures to psychosocial stress and environmental toxins—all of which have significant negative developmental impact—are likely to be involved.

The effects of elevated stress on child-caregiver relationships appear to be particularly detrimental, unsurprising in that nurturing and supportive caregiver relationships are foundational for healthy development in early childhood. For adults whose job options are unconducive to their role as parents (such as working multiple jobs or night shift hours), or for whom family support is unavailable, or for those do not have the material resources they need, the resulting stress may result in sleep disruption, depression, and anxiety—all of which translate to poor developmental trajectories for their children.

Other health and developmental risks often associated with poverty include lead and other pollutants in air and water, poor nutrition (often related to living in “food desert” areas where healthy foods such as fresh fruits and vegetables are scarce), neighborhood violence, and trauma. “Toxic stress” that exceeds a child’s ability to adapt can occur when the burden of stressful life experience overwhelms the brain’s regulatory capacity, or when the compensatory abilities of brain and body are compromised. A lack of cognitive stimulation (due to such factors as the absence of books and educational materials in the home, poor immersion in language, and a lack of after school or other enrichment activities) or disruption of sleep and circadian rhythms (by neighborhood noise or parents’ irregular work schedules) is likely to impact brain development and emotional and behavioral regulation when these systems are rapidly developing.

How the Environment Shapes the Developing Brain

Building on a robust body of literature in the behavioral sciences, developmental neuroscientists have begun to investigate whether tangible effects of poverty and adversity can be detected in the structure and function of the developing brain. A growing body of evidence demonstrates quantifiable relationships between adverse environmental exposures and alterations in neurodevelopment visible in brain scans.

Work in animal models has shown that environmental exposures influence the sculpting of neural circuits, particularly during early developmental “sensitive” periods when the brain is uniquely malleable. This sculpting occurs through processes such as neurogenesis (the sprouting of new brain cells), synaptogenesis (the growing of new connections between brain cells), and synaptic pruning (the elimination of less-used connections between brain cells to enhance efficiency of communication among neurons and in brain circuits). The environmental influence on this shaping process is thought to prepare the organism for adaptation to experiences and challenges it is likely to encounter in the future.

In human studies during childhood, developmental neuroscientists have used tools such as electroencephalography (EEG) and both structural and functional magnetic resonance neuroimaging (sMRI/fMRI) to show an association between early exposure to poverty and changes in brain structures critical for emotion regulation and cognitive function. For example, research has linked early poverty to a reduction in the size of the hippocampus, a brain region critical for healthy stress response and memory function. Further, studies using both EEG and fMRI have shown different patterns of brain activation in response to stimuli that evoke emotion or the need for emotional regulation.

Children growing up in poverty showed greater amygdala activity in response to threatening stimuli. Researchers have also found an association between early poverty and alterations in brain circuits that are important for experiencing emotions, generating adaptive behavior patterns, and learning. These changes include reduction in the connections between the hippocampus and other brain regions, such as the prefrontal cortex and the anterior cingulate, that support cognition.

As environmental shaping helps prepare an organism for its expected future, such stress-related differences in brain structure and function might be adopted to help a child manage uncertainty or respond to difficult circumstances later on. Over time or in response to chronic exposure to stress, however, adversity may also contribute to enduring disruptions in physical and mental health or in cognitive and emotional function.

There is evidence suggesting that the link between early poverty and later psychopathology is mediated through some of the alterations in brain structure and function described above. Findings of this nature have re-ignited public health attention to the problem of child poverty; their insights into the mechanistic pathways of poverty’s deleterious effects on the brain pave the way to more directed targets for prevention and early intervention.

Studies of Mechanisms

As with brain development, while the association between exposure to poverty and negative developmental child outcomes have been apparent for many decades, the underlying cellular-level and psychosocial processes are more elusive. Numerous mechanisms appear to be involved. For example, work in both humans and animals has shown that early exposure to enriched versus depleted environments, as well as variations in maternal care, can change the expression of key genes (i.e., turning on and off the production of proteins encoded by each gene) that are involved in brain development and function.

Such epigenetic mechanisms represent an interface at which nature and nurture interact. For example: A healthy response to stress requires activation of a brain system called the hypothalamic pituitary adrenal axis (HPA axis); it regulates the release of the brain hormone cortisol, which helps prepare the body for adaptive coping. Excessive or prolonged HPA activation (such as the chronic stress that commonly accompanies poverty), generates too much cortisol, and can change gene expression in a way that causes lasting disruptions in hippocampal structure and function.

A similar process has been described in immune system reactivity, where chronic exposure to poverty and related stresses results in a “pro-inflammatory” state where the immune system remains activated, even without microbial threats. This chronic low level of elevated inflammation poses long-term health risks.

In addition, living in poverty is associated with disruptions in the sleep-wake cycle; noise and light and patterns of household function that accompany challenging work hours (e.g., late shift work) can reduce the amount of sleep for children as well as adults. These disruptions have their own impact on brain circuits, interfering with neural restorative processes that accompany regular sleep and are critical for learning and emotion.

As noted above, poverty is frequently associated with exposure to environmental toxins known to harm brain development, such as lead, polycyclic aromatic hydrocarbons (produced when oil, gas, and tobacco are burned), and nitrogen dioxide (present in air pollution). All too frequently, poverty also means reduced access to adequate nutrition, green space, and health care, all of which can directly and indirectly impact brain and overall development.

Understanding the mechanisms of risk is complicated by the fact that poverty typically brings many risks at once, making it difficult to determine which risk factor drives which specific negative outcome (e.g., emotion dysregulation, failure to achieve potential), or whether multiple exposures have synergistic effects. And while causality may be suggested by association, it can be clearly established only with experimental designs that measure key outcomes before and after exposure to risk factors. Such studies are very rare but have been possible in the face of an environmental change (e.g., income increases brought out by an economic boon to a community, a pandemic, or policy change, or natural or man-made disasters that bring about social adversity in a previously well-resourced community).

Knowledge gaps notwithstanding, the robust evidence for a connection between poverty and poor physical and developmental outcomes, and the high proportion of US children born into poverty, argue an ethical imperative to determine whether ensuring economic equity would bring benefits comparable to avoidance of toxic exposures and iron deficiency, which is now the standard of care and practice. Further enhancing income may also be a first step towards ameliorating other negative social forces and psychosocial support of parents during their children’s first years of life (Early Head Start and Healthy Families America); and educational support of preschoolers (Head Start). Each program has overwhelmingly demonstrated incremental improvements in the average outcomes of the children such as overall achievement and lower rates of psychopathology. But they have not been nearly enough to close the developmental and mental health gap between children who grow up in underprivileged environments and those who do not.

Interventions designed to enhance the parent-child relationship and reduce the likelihood of severe adverse experiences, such as child abuse and neglect, have proven a feasible and effective next-line-of-defense in the roster of federal programs for children in poverty. Ranging from home-visiting programs to live coaching during parent-child interactions, they aim to enhance emotional such as environmental and racial injustices associated with low SES. Studies that provide income transfers to young families living in poverty have provided some promising initial results, but most have not followed children long enough to show the enduring neural and mental health benefits.

Understanding the pathways and mechanisms of poverty’s negative effects on the developing child is essential if we are to understand the importance of alleviation of risks associated with poverty and develop more cost-effective and targeted preventions and early interventions. That the direct consequences of economic insufficiency on brain development are entirely avoidable in the US, given its wealth as a nation, underscores the importance of these scientific endeavors.

Interventions to Protect Developing Children

Despite the growing knowledge base, there has been surprisingly little sustained public interest or investment in supporting robust programs to interrupt poverty’s deleterious impact on children. A notable exception is the “War on Poverty” with its federal programs for children living below the poverty line, initiated by President Lyndon Johnson in 1964 and still operational in all 50 states.

Temporary Assistance for Needy Families (TANF) and the annual Child Tax Credit, contemporary mechanisms for direct cash transfers to impoverished families, evolved from the War on Poverty. Other federal programs have focused on consequences of poverty that damage the development of children, including nutritional support (the Women, Infants, and Children program WIC); educational connection and warmth between parent and child and teach caregivers how to set nurturing but firm limits. These strategies have shown strong efficacy in buffering the negative emotional impact of poverty.

Such interventions may be delivered in clinical settings or in the home or, more recently, by video conferencing. Extending them through community settings such as school or primary care sites will facilitate access to high-risk populations. There are now a number of empirically tested (and proven effective) models of this type of preventive intervention whose low cost makes them feasible for broad delivery with minimal social investment (through taxpayer dollars into social programs) and a high return on that investment. The question becomes: How to emphasize the importance of these interventions and their effectiveness to administrators responsible for child health and well-being?

Science Policy Gap

In regard to the above question, the gap between scientific advances and changes in social policy and healthcare practices is well-known. The field of implementation science was developed to address it by identifying barriers to the uptake of advances in medicine, social science, and psychology by practitioners and healthcare systems. This gap can be even more daunting in the area of public policy, where political perspectives and agendas can obstruct the integration of scientific findings.

In the area of poverty and child development, the science-policy gap is strongly influenced by political philosophies and belief systems about the merits and liabilities of social safety nets. Even tangible economic benefits—compelling data that early interventions for children living in poverty result in a high return on investment and significant savings in tax-payer dollars over the long-term when they are used to fund these social programs—often fail to influence policy in a logical manner.

Changing Social Attitudes

More generally, stereotypes about poverty continue to thwart progress in this area. The idea that people live in poverty because they are unmotivated to work, or fail to take responsibility for themselves, or are genetically destined to fail, often drives social investment or lack thereof, even when it affects the well-being of young children. The commonly held misconception that people living in poverty are predominantly racial/ethnic minorities in cities may fuel beliefs based on implicit or explicit bias. In fact, the majority of people in poverty in the

supporting robust programs to interrupt poverty’s impact on children.

US are white and live in rural areas. This is because even though the percentage of racial and ethnic minorities living in poverty is higher than the percentage of white individuals, there are a larger number of white individuals in the US. For example, in 2020, 15.6 percent of white non-Hispanic households were living on $24,999 or less a year, with 29.7 percent of household identifying as black were living at or below the same income levels. However, in terms of numbers of households, this reflects 13.3 million households identifying as white non-Hispanic and 5.2 million households identifying as Black. This is not to suggest that we should only care about poverty if it happens to majority culture individuals, but simply to point out that poverty affects people of all racial and ethnic identities in our society.

We need to develop interventions that support people facing poverty across all racial, ethnic, geographic, and other identity lines. Greater attention to the forces that drive individuals into poverty, such as a lack of intergenerational transmission of wealth, systemic racism and discrimination, social rejection, drug and alcohol abuse, and limitations in opportunity, is of paramount importance when addressing this problem on a larger scale.

Otherwise, the unacceptably high proportion of young children—the next generation of adults— growing up in poverty represents our future. An understanding of how powerfully early life experiences shape the development of their minds and brains provides compelling evidence of what can and needs to be protected, and points to a great opportunity for building a healthier and more productive society. The public needs to know. l

More than suffer from pain. Our psychologist College’s Cognitive Neuroscience relationship feelings, and the actual what pain and how new leading to than 20 percent of US adults from some form of chronic author, a cognitive psychologist and head of Dartmouth Cognitive and Affective Neuroscience Lab, examines the relationship among our thoughts, and beliefs about pain and actual physical pain that we feel, pain looks like in the brain, new research findings are to effective new treatments.

PAIN IS AN INCONVENIENT REALITY. It is the most common reason people seek medical attention, affecting more people than diabetes, heart disease, and cancer combined. It exacts enormous costs in quality of life, not just for the pain sufferer, but for their families, caregivers, and communities. It is a symptom in hundreds of disorders, cutting across virtually every specialty in medicine. It is also intimately related to the ongoing opioid epidemic in America and beyond.

By Tor D. Wager, Ph.D.

Patients are routinely prescribed opioids for acute pain after injury or surgery, and a substantial fraction of them will go on to become chronic opioid users. For some of these, the effects are devastating: In 2021, America saw over 100,000 drug overdose-related deaths, 75 percent of them caused by opioids, and the numbers have been climbing each year. For those who survive, opioid use takes a toll as well, causing changes in the brain that make it more difficult to work and to find enjoyment in daily life. Pain and pleasure are two fundamental forces that motivate us. Our history with pain goes back to our most ancient ancestors: Protozoa, sponges, insects, crustaceans, and more possess the same families of ion channels that enable pain in humans. These channels sense harmrelated signals in the environment, like noxious chemicals, and turn them into electrical signals in the nervous system, providing the basis for escape, avoidance, and learning. The dual teachers of pain and reward are at the core of our brain’s ability to rewire itself to avoid threats and pursue opportunities in changing environments.

Pain Falls Between the Cracks

In spite of its fundamental importance, pain has fallen between the cracks in our scientific disciplines and healthcare systems. Most medical schools provide only a handful of hours of pain education, distributed across four years. If a peripheral cause cannot be determined and eliminated, chronic pain patients are shuttled across departments, their pain “managed” but with little hope for a cure. They are often referred to psychiatrists, but few psychiatrists are equipped to deal with chronic pain. Pain barely appears in the Diagnostic and Statistical Manual of Mental Disorders and is absent from the Research Domain Criterion framework, although in real life it co-occurs substantially with depression and anxiety. In fact, there is evidence that links between pain and mental illness are causal and bidirectional Psychology also has a blind spot when it comes to pain. Pain researchers are uncommon in academic psychology departments and neuroscience programs. And though many forms of chronic pain are treatable with behavioral methods, clinical training programs equip newly minted psychologists to treat anxiety, depression, obsessivecompulsive disorder, panic disorder, personality disorders and more— but not pain. There is no National Institute of Pain.

Pain is a central part of being human: Many of our oldest philosophical and spiritual traditions address ways to manage, avoid, and sometimes accept it. The Bhagavad Gita, for instance, instructs us to be at peace “in cold and heat, in pleasure and pain, in honor and dishonor.” The Roman stoic Marcus Aurelius wrote in the book Meditations, “Pain is neither intolerable nor everlasting, if thou bearest in mind that it has its limits, and if thou addest nothing to it in imagination…” These traditions teach us how to think about suffering and how to tap into our brains’ innate capacity to self-regulate. Although our ancestors knew nothing of the brain pathways that create pain, the central principles they taught and lived by have been rediscovered and adapted by modern approaches to pain treatment.

The Oldest Cure in the Book

Morphine–derived from the opium poppy–is the oldest drug in modern medicine’s pharmacopeia. Its medicinal use dates to ancient Egypt. It also has long been known that morphine and other opioids are addictive. One of the earliest synthetic drug formulations— developed by Bayer in the 1890s— was designed to make morphine less addictive and marketed as a “soothing syrup” to help children sleep. That drug is heroin, which is illegal in the US because of its high risk for abuse.

The evidence from randomized clinical trials of opioid treatment shows that its benefits are surprisingly modest. In the most recent meta-analysis, pain control was less than one point on a ten-point scale, and its efficacy declined with prolonged treatment. Meanwhile, basic research indicates that opioids can sensitize nociceptive neurons in the spinal cord, increase neuroinflammation, and increase pain in the long-term. The dose required to maintain the same degree of pain control rises dramatically (there is a 40-fold difference between the lowest and highest doses offered by some manufacturers), because the nervous system desensitizes to opioids when they are used continuously.

Desensitization to opioids is a powerful example of an opponent process, in which short-term effects (pain relief and possibly a “high”) are counteracted by long-term adaptations (desensitization). The net result with opioids is short-term pain relief but long-term anhedonia— reduced joy and motivation, also called hyperkatifeia—along with uncontrolled pain. The longer one takes the drug, the lower the benefits and greater the costs. After taking opioids even for a short period of time in some studies, individuals experience increases in both pain sensitivity and negative emotion unless the drugs are actively “on board.”

Other popular “painkillers” don’t work as well as it might seem, either. How about an ibuprofen or acetaminophen for low back pain? Their effects are barely better than taking a placebo pill. With regard to neuropathic pain, which is caused by a lesion or disease in the central nervous system (e.g., diabetes, stroke, or nerve injury), antidepressants, gabapentinoids, and even opioids are prescribed. But whichever drug is used, the effects are modest on average. How about cannabinoids? It’s taken as established truth that they are good for pain. But in a recent meta-analysis, they provided only a three-to-four percent improvement over placebo.

The pharmaceutical industry has spent billions of dollars developing pain treatments, with (at least so far) unimpressive results. Every drug has side effects; many are ineffective. Many drug companies have simply stopped trying to advance new therapeutics for managing pain. Clinical trials are expensive, so most pain treatments will never be vetted as extensively as drugs or reported in major medical journals, particularly if the treatments are principles and practices that are freely available. All this work has given us some good ideas about what doesn’t work very well.

Clues from the Brain

Research across sensory modalities has found that our perceptions are constructions: The brain interprets sensory input through a lens of memory, logic, and emotion. Our perception is not a veridical reflection of the world, but rather a guess, an inference, about what is really there based on multiple context clues. That’s why we see faces, effortlessly and automatically, in particular configurations of clouds. And it is why people with some pain conditions feel pain when they look at emotionally distressing pictures These “biases” help us act not just on what is immediately presented to our senses, but what is likely to be there, and they help us predict and respond to situational demands in advance: They alter our pain sensitivity to prepare for action in a dangerous situation.

Because pain is a construction based only partly on input from the body, the brain has the capacity to alter pain and the feelings and motivations surrounding it in multiple ways. Descending modulatory systems can enhance or inhibit pain-related signals in the spinal cord before they even reach the brain. The brain maintains a balance between promoting and inhibiting pain, and nerve injuries can shift the balance towards a pain facilitation state

Essentially, the brain has “decided” that when an injury is perceived, it should feel pain, which can promote recovery. Pain also drives decisionmaking at several levels: what we escape now, what we avoid in the future, for which threats we should be vigilant, and what cues signal danger. Pain is the experience that drives fear-conditioning and other forms of threat-learning. The activity in these systems is also subject to construction, as the brain “decides” which sensations are truly threats to the body and what defensive adaptations are necessary to prevent future harm.

These principles suggest why pain-related brain activity is sensitive to context, past experiences, and suggestion. Giving a placebo treatment—e.g., a sugar pill or inert ointment—can reduce activity in brain areas involved in constructing the pain experience and induce the release of endogenous opioids and dopamine. In some studies, placebo treatments coupled with suggestions about increases and decreases in pain can affect pain-related activity in the human spinal cord. These neurobiological effects play out in real life: Clinically, placebo treatments can reduce pain related to migraines and other headaches, osteoarthritis, gastrointestinal pain, and more.

Placebo treatments and interventions based on manipulation of the social and environmental context don’t all affect pain by the same neurological pathways. For example, suggestions about social context (how other people perceive pain) and classical conditioning can both exert substantial effects on the experience of pain and even autonomic responses to painful events. But their effects on pain are mediated by different brain systems; prefrontal cortical systems are involved in social cognition, and hindbrain systems in associative learning. There appears to be no “final common pathway.” But behind all these interventions is the brain’s mental model of the painful event and whether it is conceived of as damaging or dangerous, now or in the future.

Emerging research on underlying brain systems supports the idea that chronic pain, even more strongly than pain evoked acutely by somatic stimuli, is an integrative construction that extends beyond the detection of painful stimuli. Neuroimaging of pain sensations in hypersensitive patients has found enhanced activity in brain regions that also encode pain in healthy people. Moreover, new studies have found that chronic pain induces changes in affective and motivational circuits that don’t respond to noxious input—that is, their activity doesn’t increase as one turns up the level of painful heat or pressure applied to the body. These circuits include the ventromedial prefrontal cortex (vmPFC), posterior cingulate, nucleus accumbens, and hippocampus.

Whether back pain progresses from acute to chronic, for example, appears to be related to the strength of functional connectivity between the vmPFC and the nucleus accumbens, as measured with fMRI. Stronger correlations between activity in the vmPFC and pain encoding regions have been found in chronic back pain, fibromyalgia, failed back surgery, and more. Other studies suggest that pain is not localized to any one brain network but is instead an altered global brain state that is defined by a pattern of interconnections across many regions spanning the brain.

Some of the key brain areas for chronic pain intersect with what has come to be known as the “default mode network” (DMN), so named because it is primarily active when a person is simply resting without any external stimulation (i.e., daydreaming, mind-wandering, etc.). This network seems to encode, in various ways, our conception of situations—mental conceptions of the environment and our capacity to act in it—particularly as they relate to the self and future well-being. The vmPFC is a key “node” in the DMN. Patterns of activity in the vmPFC encode our personal memories, the value we place on rewards, imagined futures, the hidden causes to which we attribute rewarding or punishing outcomes, and the meaning we ascribe to events. But the vmPFC is also a primary driver of autonomic activity and hormone release; its response during stress determines heart rate increases and the brainstem activity that controls autonomic output. It is also among the brain areas most strongly associated with immune responses My colleagues and I have proposed that the DMN plays a central role in constructing situational meaning, linking conceptual thought with the mobilization of physiological resources to meet the demands that bear on one’s personal well-being. This hypothesis gives vmPFC and the DMN a critical role in avoidance learning, linking actions and other cues (sensations, places) to danger, and guiding actions to avoid threats. This inherently requires inference or guesswork because no two situations are the same. If you injure your back alpine skiing, should you be afraid of skiing again?

More broadly, the vmPFC helps determine how we generalize our experiences, which, in turn, depends on what we think was the underlying cause and whether it will recur in new scenarios. For example, in the case of back surgery for chronic pain, our brain contains a mental model of this situation—local injury and inflammation, with the expectation that the pain will last for a few months and decrease gradually as the injury heals. When you feel local back pain, you are not surprised because you attribute it to the model. You take a walk and feel some pain, but this is normal—it fits within the model. But what happens if the pain starts to get worse again or spreads to other parts of the body? This might prompt a more sinister interpretation: that the body is and will remain dysregulated in ways unexplainable by medicine.

This view might be reinforced by physicians who are unable to identify a physiological cause for the pain. As one patient described it, “I’ve always been told that I’m broken.”

Once pain has persisted for a long time, clinicians might say that until a cause is found, the patient will always be in pain. Others might say that pain is a sign of bodily injury, so he or she should avoid doing something if it hurts. While these statements may be reasonable guesses, they have powerful nocebo (the opposite of placebo) effects: The suggestion of ongoing harm can enhance threat signaling in brain and body. More perniciously, they reinforce maladaptive beliefs about the meaning of pain, as a sign of bodily harm or dysfunction and an indicator of future dysfunction. My colleagues and I think that such mental constructs are maintained in the DMN, forging the link between this system and chronic pain.

What Works

A family friend recently wrote me about her experience with Complex Regional Pain Syndrome, a form of neuropathic pain that she developed after a cycling accident. She tried over 20 unsuccessful treatments, including three stellate ganglion blocks, 200 hours of physical therapy, yoga, direct current microstimulation, and pulsed electromagnetic field therapy. At the end of this odyssey, she has been able to substantially reduce her pain, return to work, and eliminate all of the invasive interventions. What worked? It’s not clear that any single treatment was a magic bullet. In this journey, she established a “new brainbased belief system,” thinking of her pain and its peripheral signs— including inflammation and other visible signs—as the result of an unconscious threat response in her brain. She framed recovery as an “argument with the body,” an attempt to convince her brain that the injury is healed and there is no longer a need to mount a threat response. And “when the argument was won, acceptance. Relief.”

What works may be different for each individual, but a common principle may be changing those systems in the brain that maintain the belief that the body is under threat. But what is convincing to one person (or one person’s unconscious brain) may not be to another. I’ve heard many stories of people who have been in chronic pain for years, finding substantial relief in a single session of therapy, or after reading a book whose ideas resonate. Others need more support and personalized guidance.

My laboratory has recently completed a study of a treatment called Pain Reprocessing Therapy (PRT), a combined psychological and behavioral treatment that is designed to do two things. The first step is to help patients realize that pain does not reflect tissue damage or harm. It is a “false alarm” created by the brain, unpleasant but not dangerous. The second step is to put that realization into practice by performing the movements and exposing oneself to the situations that created pain and fear in the past. In a randomized clinical trial, patients who received PRT achieved remarkable reductions in pain. Though the participants had been in pain for ten years on average, two thirds were pain-free or nearly so after four weeks of treatment (eight sessions). Patients randomized to placebo or usual care showed much more modest gains.

Like other psychological treatments, PRT gives people principles to practice in their daily lives, so benefits didn’t end after the eight sessions were finished. They were nearly as large a year later. Using fMRI after treatment, we found reductions in pain-encoding parts of the anterior insula and anterior cingulate, the two areas most strongly associated with sensing pain and regulation of the autonomic nervous system. And while there were many auxiliary benefits (improved mood, sleep, and function), the strongest predictor of pain reduction was change in beliefs about the causes and meaning of pain.

Recent studies have also found substantial improvements with other psychological and behavioral treatments. Some methods, such as Emotional Awareness and Expression Therapy, focus on associations between emotional trauma and pain. Others, like Mindfulness-Oriented Recovery Enhancement (MORE), aim to change the meaning of pain and stressors. In one recent study, MORE substantially reduced both pain and opioid use. The effects were larger the longer the follow- up; at nine months, MORE cut opioid use in half.

These approaches, which combine methods used in cognitive behavioral therapy (CBT) in a novel way, are not yet standard practice in the psychological treatment of pain. But they appear to work substantially better: While standard psychological modalities yield only modest effects (comparable to or weaker than the drug effects mentioned above), these new treatments have shown substantial and durable benefits, at least in initial studies. Many questions remain about the types of chronic pain for which each of the new treatments is helpful, who will benefit most, how extensive the treatment must be, and how easily people can be trained to deliver it.

As for CBT and other standard psychological approaches to pain, the lack of compelling data does not mean they cannot be important treatment avenues for many people. Such treatments are not standardized the way that drug treatment is: They are tailored to the individual patient, and many individual practitioners have converged on principles similar to those in PRT or MORE. This suggests that the optimal ingredients of CBT for pain remain to be discovered.

Several principles underlying psychological treatments like PRT depart from standard pain psychology. First, they provide an explanation for chronic pain that acknowledges its reality while affirming that it is not a sign of damage to the body but the result of sensitization in neural circuits, drawing on findings in neuroscience. The belief that “pain does not equal damage” helps patients see that pain, while unpleasant, can be safe. Second, it encourages them to turn their attention back to the body by practicing mindful attention to the physical sensations of emotion and of pain, and even engage in painful movements deliberately.

These clinical effects dovetail with findings from my laboratory that focusing on the non-affective aspects of pain (i.e., treating it as an “interesting sensory experience”) can produce more pain relief than turning attention away from the body (e.g., distraction). By the same token, we’ve found that mindful acceptance of pain is one of the most potent interventions for reducing painrelated brain activity. If pain is viewed as fundamentally safe, it’s okay to perform painful movements; this pain exposure may be a key to re-training the brain towards a less sensitive state.

Exposure has two other advantages: Putting nascent beliefs into practice, it amplifies commitment to the idea that pain is safe. And it provides somatosensory input to help the brain recognize pain signals as part of the normal sensory landscape. Beyond overcoming negative beliefs, some emerging treatments focus on reengaging positive experiences—like the practice of “savoring” positive experiences (cultivating enjoyment) in MOST or exploring pain sensations with a curious or even playful attitude in PRT (“wow, look at my brain tricking me!”)— ideas antithetical to regarding pain as a threat.

We have a long way to go in understanding how to help those who suffer from chronic pain find their individual paths to recovery. But advances in that direction have been significant, demonstrating that such pain is real but that its root causes are in the brain rather than in local tissue—i.e., “where it hurts.” Innovations in pain psychology have shown that even with acute paininducing pathology after an injury, cognitive approaches can re-shape neural circuits to minimize suffering and promote recovery.

At the same time, researchers into the biology of chronic pain are developing biomarkers to sharpen diagnosis and prognosis, and track treatment response on a larger scale than ever before. Toward that end, the UK Biobank has gathered genetic, clinical, neuroimaging, and other measures on approximately 500,000 individuals, including those with dozens of pain disorders. The Acute to Chronic Pain Signatures program is taking a comprehensive approach to understanding vulnerability to post-surgical chronic pain, using neuroimaging, metabolomics, transcriptomics, lipidomics, and systemic inflammation data in more than 2,000 patients followed over time. All in all, the future of pain treatment is looking brighter than it ever has—and there is not a moment to lose in moving forward. l